Alzheimer's Disease (AD) is a devastating illness projected to affect 16 million Americans by 2050;at an estimated cost of $100 billion annually. Central to the disease course is a decline in cognitive abilities;including the acquisition and retrieval of memories, impairments in language, judgment, and behavior. These behavioral changes are accompanied by selective dysfunction and neuronal death in brain regions critical for memory and cognition, such as the hippocampus and cholinergic regions. The AD hippocampus is also one of the CMS areas most affected by the characteristic plaques of misfolded amyloid beta (Abeta), a cleavage product of the amyloid precursor protein (APR). This protein fragment is widely recognized as one major neurotoxic agent of AD. However, recent research suggests that the plaques are not the offending species;rather protofibrillar intermediates (oligomeric) are responsible for the changes associated with AD progression. However, how the oligomeric form of the A[unreadable] protein induces overwhelming, specific neuronal dysfunctions responsible for memory deficits and eventually neuron cell death is not yet understood. The central hypothesis of my project is that oligomeric amyloid beta (Abeta 1-42) perturbs synaptic plasticity and disrupts memory through abnormal induction of calcineurin (CaN) activity. This phosphatase is an important negative regulator of synaptic plasticity, through its inactivation of CREB, which is necessary for LTP. Following up on highly suggestive preliminary data, I will investigate the aberrant activation of CaN as a critical step in Abeta's neurotoxic action. My project follows three specific aims. Firstly, determine the effect of monomeric vs. oligomeric vs. fibrillar Abeta on CaN activity and CaN dependent memory deficits in wild-type mice. Secondly, to test the hypothesis that there is a direct relationship between the occurrences of oligomeric A[unreadable], elevated CaN activity/signaling, and deteriorating memory function in an animal model of AD. Finally, to investigate the effect of oxidative metabolites on the formation of oligomeric Abeta. My dissertational research will contribute to a fuller understanding of mechanisms underlying oligomeric formation and memory disrupting abilities of Abeta;and hopefully identify ways to target CaN in order to prevent cognitive dysfunction. The research described in this application is significant, because it will illustrate sensible pharmacological targets and stimulate the development of novel therapies to halt Abeta neurotoxicity. Such treatments would improve the health of AD patients and dramatically decrease the overwhelming burden on public health.